L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway
JournalCancer Management and Research
PublisherDove Medical Press Ltd
MetadataShow full item record
AbstractBackground: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The poor prognosis of this disease highlights the urgent need to develop more effective therapies. Activation of the STAT3 represents a potential drug target for pancreatic cancer therapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking. Methods: Through bioassay screening and molecular docking, we identified a small molecule L61H46 that can potently target constitutive STAT3 signaling and kill human pancreatic cancer cells in vitro and in vivo. Results: L61H46 effectively reduced colony formation and the viability of pancreatic cancer cells in a dose-dependent manner with half-maximal inhibitory concentration (IC 50 ) values in the range between 0.86 and 2.83 µM. L61H46 significantly inhibited STAT3 phosphorylation (Tyr705) and the subsequent nucleus translocation but did not downregulate STAT1 phosphorylation. Moreover, L61H46 demonstrated a potent activity in suppressing pancreatic tumor growth in BXPC-3 xenograft model in vivo. Furthermore, L61H46 showed no signs of adverse effects on liver, heart, and kidney cells in vivo. Conclusion: Collectively, our results suggest that L61H46 could be further optimized into a highly potent STAT3 inhibitor for the treatment of pancreatic cancer. Copyright 2018 Bai et al.
SponsorsThis research was supported by the Zhejiang Provincial Natural Science Fund (LY18H160047, LY16H160052, and LY17H160055), Medical Scientific Research Fund of Zhejiang Province (2017192276), and Wenzhou Science and Technology Project (Y20170176, Y20170280, and Y20170174).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85044780081&doi=10.2147%2fCMAR.S159090&partnerID=40&md5=9ccee911c13551ec93effe4fbd8c3622; http://hdl.handle.net/10713/9482